Non-peptide based C5a receptor antagonists have been described in the literature (e.g., Sumichika, H., et al., J. Biol. Chem. (2002), 277, 49403-49407), and have been reported as being effective for treating endotoxic shock in rats (Stracham, A. J., et al., J of Immunol. (2000), 164(12): 6560-6565); and for treating IBD in a rat model (Woodruff, T. M., et al., J of Immunol., 2003, 171: 5514-5520). Non-peptide based C5a receptor modulators also have been described in the patent literature by Neurogen Corporation, (e.g., WO 2004/043925, WO 2004/018460, WO 2005/007087, WO 03/082826, WO 03/08828, WO 02/49993, WO 03/084524); Dompe S.P.A. (WO 02/029187); The University of Queenland (WO 2004/100975); and ChemoCentryx, Inc. (WO 2010/075257 and WO 2011/163640).
There is considerable experimental evidence in the literature that implicates increased levels of C5a with a number of diseases and disorders, in particular in autoimmune and inflammatory diseases and disorders. There is a need in the art for new small organic molecule modulators, e.g., agonists, partial agonists, and preferably antagonists, of the C5a receptor (C5aR) that are useful for inhibiting pathogenic events, e.g., chemotaxis, associated with increased levels anaphylatoxin activity.
Despite the availability of C5aR antagonist compounds as described in WO 2010/075257 and WO 2011/163640, there remains a need for related compounds having improved solubility profiles that can be formulated in a manner suitable for intravenous delivery and also provide a therapeutic benefit similar to the compounds in WO 2010/075257 and WO 2011/163640.